New N⁴‐Hydroxycytidine Derivatives: Synthesis and Antiviral Activity.

Abstract

New N 4 -Hydroxycytidine Derivatives: Synthesis and Antiviral Activity. -Various derivatives of the antiviral N 4 -hydroxycytidine (Ia) are prepared [cf. (Ib,c) and (II)]. Investigations concerning their pharmacological activity reveal that the acyloxy derivatives of type (I) exhihit potent antiviral effects, whereas the 5'-phosphonates are more cytotoxic than the parent compound (Ia). -(IVANOV, M. A.; ANTONOVA, E. V.; MAKSIMOV, A. V.; PIGUSOVA, L. K.; BELANOV, E. F.; ALEKSANDROVA*, L. A.; Collect.

Developing a direct acting, orally available antiviral agent in a pandemic: the evolution of molnupiravir as a potential treatment for COVID-19

“…In 2013 we began screening ribonucleoside analogs for activity against alphaviruses and quickly identified N4-hydroxycytidine (identified internally as EIDD-1931) as a lead with activity against the New World encephalitic alphaviruses as well as chikungunya virus. Before this there had been a number of studies demonstrating the activity and favorable cytotoxicity profile of EIDD-1931 in cell culture models of infection [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. Pharmacokinetic and distribution studies in mice, rats, ferrets and dogs revealed that EIDD-1931 was orally bioavailable, widely distributed to organs including the lungs and appeared to be actively transported into the CNS where it was quickly anabolized to the active 5′triphosphate [ 7 • , 8 , 10 •• ].…”

Pyrimidine Ribonucleotides with Enhanced Selectivity as P2Y6 Receptor Agonists: Novel 4-Alkyloxyimino, (S)-Methanocarba, and 5′-Triphosphate γ-Ester Modifications

“…The synthesis of several of the pyrimidine nucleotides was reported in previous studies of the P2Y receptor (3, 5, 6, 8, 10, 19, 21, and 26). [14][15][16] 5-Iodouridine 34 was available from commercial sources, while the 4-methoxyimino derivative 36 and (S)-methanocarbauridine 41 were prepared as described, 19,25 and compounds 37-39 were prepared by the same procedure as 36. Compounds 34 and 36 were converted to the R,β-methylene diphosphonate analogues 11 and 16, respectively, by a carbodiimide condensation.…”

“…Compound 36 was synthesized as reported. 19,25 Other reagents and solvents were purchased from Sigma-Aldrich (St. Louis, MO).…”

“…The resulting solid was removed by filtration, and the filtrate was purified by semipreparative HPLC as described above to obtain 22 (1.2 mg, 27%) as a white solid. 1 P 1 -Uridine 5 0 -P 3 -Cyclohexyltriphosphate Triethylammonium Salt (25). Compound 1 (4 mg, 0.010 mmol) was exchanged to the tributylammonium salt form.…”

“…5-Iodouridine 34 was purchased from Berry Associates (Ann Arbor, MI). Compound 36 was synthesized as reported. , Other reagents and solvents were purchased from Sigma-Aldrich (St. Louis, MO).…”